Antineurodegenerative ergoline derivatives

ABSTRACT

The present invention provides the new use in the treatment of neurodegenerative diseases with ergoline derivatives of formula (I) ##STR1## wherein R 1  represents a hydrogen atom or a linear or branched C 1  -C 5  alkyl or C 2  -C 5  alkenyl group optionally substituted with a C 3  -C 7  cycloalkyl, a hydroxy group or a R 3  -substituted phenyl group wherein R 3  is a hydroxy or a hydroxymethyl group; R 2  represents a hydrogen atom or a linear or branched C 1  -C 5  alkyl or a C 2  -C 5  alkenyl group optionally substituted with a hydroxy group, or a R 3  -substituted phenyl group wherein R 3  is as above defined, or with a C 1  -C 5  alkoxy group; the symbols--at positions 2,3 and 8, 9 independently denote a single or double chemical bond and Z represents a group (CH 2 ) n  OH, wherein n is 0 or an integer from 1 to 3, or a group C(R 4 ) 2  OH wherein R 4  is a C 1  -C 5  alkyl or a phenyl group, or a pharmaceutically acceptable salt thereof. Some compounds of formula (I) are novel. Processes for their preparation and pharmaceutical compositions containing them are also described.

This application is a 371 of PCT/EP97/02955 filed May 29, 1997, now WO98/00424 Jan. 08, 1998.

The present invention relates to the treatment of neurodegenerativediseases employing ergoline derivatives, to new ergoline derivatives forsuch a treatment, to a process for preparing them and to theirpharmaceutical acceptable salts.

The present invention relates to the therapeutic use, in the treatmentof neurodegenerative diseases, of ergoline derivatives of formula I##STR2## wherein R₁ represents a hydrogen atom or a linear or branchedC₁ -C₅ alkyl or C₂ -C₅ alkenyl group optionally substituted with a C₃-C₇ cycloalkyl, a hydroxy group or a R₃ - substituted phenyl groupwherein R₃ is a hydroxy or a hydroxymethyl group;

R₂ represents a hydrogen atom or a linear or branched C₁ -C₅ alkyl or aC₂ -C₅ alkenyl group optionally substituted with a hydroxy group, a R₃-substituted phenyl group wherein R₃ is as above defined, or with a C₁-C₅ alkoxy group; the symbols--at positions 2,3 and 8, 9 independentlydenote a single or double chemical bond and Z represents a group(CH₂)_(n) OH, wherein n is 0 or an integer from 1 to 3, or a groupC(R₄)₂ OH wherein R₄ is a C₁ -C₅ alkyl or a phenyl group, or apharmaceutically acceptable salt thereof.

The wavy line (˜˜) in formula I indicates that the substituent in the 8-or 10-position may be either in the α-configuration, i.e. below theplane of the ring, or in the β-configuration, i.e. above the plane ofthe ring.

In a further aspect of the present invention, there are provided novelergoline derivatives of formula I as above defined, characterised inthat the following compounds are excluded:

6-methyl-8β-hydroxy-10α-methoxy-ergoline,

6-methyl-8β-hydroxymethyl-10β-methoxy-ergoline,

6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline,

6-methyl-8α-hydroxymethyl-10α-methoxy-ergoline,

6-methyl-8β-hydroxymethyl-10α-(1-methylethoxy)-ergoline ,

6-methyl-8β-hydroxymethyl-10α-hydroxy-ergoline,

6-methyl-8β-hydroxymethyl-10β-hydroxy-ergoline,

6-methyl-8β-hydroxymethyl-10α-methoxy-Δ-8,9-ergolene

8β-hydroxymethyl-10α-methoxy-ergoline,

6-methyl-8β-hydroxyethyl-10α-methoxy-ergoline, and

6-methyl-8β-hydroxymethyl-10α-propoxy-ergoline.

More preferably there are provided ergoline derivatives of formula I asabove depicted, characterised in that Z is not a hydroxy, hydroxymethylor hydroxyethyl group, when R₁ is hydrogen, or a methyl group, R₂ ishydrogen or a methyl, propyl, isopropyl group, --at 2, 3 position is adouble bond and--at 8,9 position represents a single or a double bond.

In the present specification, the term C₁ -C₅ alkyl group includesmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentylgroups and the term C₂ -C₅ alkenyl group includes 2-propenyl, 1-butenyl,1,1-dimethylallyl, 1-pentenyl, 2-pentenyl. The term C₃ -C₆ cycloalkylgroup includes cyclopropyl, cyclopentyl and cyclohexyl groups.

The R₃ substituent on the phenyl group in the meanings of R₁ and R₂ maybe in orto, meta or para position.

Pharmaceutical acceptable salts, which may be used in the acid additionsalt formation, include maleic, citric, tartaric, fumaric,methanesulphonic, acetic, benzoic, succinic, gluconic, glutamic, malic,mucoic, ascorbic as organic acids or hydrochloric, hydrobromic,sulphuric, or phosphoric as inorganic acids. Among the addition saltsobtained by employing acids, hydrochloric, methanesulphonic, citric andtartaric are the most preferred.

In the present invention, R₁ is preferably hydrogen atom, methyl, 2hydroxyethyl or (2-hydroxy-2-phenyl)ethyl group; R₂ is preferablyhydrogen atom or methyl, 1-methylethyl, propyl, 2-hydroxyethyl,3-hydroxypropyl, 2-methoxyethyl group, Z is preferably a group (CH₂)_(n)OH, or C(R₄)₂ OH, n is preferably O, 1 or 2, R₄ is preferably methyl orphenyl group.

Specific examples of the preferred compounds of the present inventionare those listed hereinunder:

1) 6-methyl-8β-hydroxy-10α-methoxy-ergoline

2) 6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline,

3) 6-methyl-8α-hydroxymethyl-10α-methoxy-ergoline,

4) 6-methyl-8β-hydroxymethyl-10α-(1-methylethoxy)-ergoline,

5) 6-methyl-8β-hydroxymethyl-10α-hydroxy-ergoline,

6) 6-methyl-8β-hydroxymethyl-10β-hydroxy-ergoline,

7) 6-methyl-8β-hydroxymethyl-10α-methoxy-Δ-8,9-ergolene

8) 8β-hydroxymethyl-10α-methoxy-ergoline,

9) 6-methyl-8β-hydroxy-10α-ethoxy-ergoline,

10) 6-methyl-8β-hydroxy-10α-propoxy-ergoline,

11) 6-methyl-8β-hydroxymethyl-10α-propoxy-ergoline,

12) 8β-hydroxy-10α-methoxy-ergoline,

13) 8β-hydroxy-10β-hydroxy-ergoline,

14) 8α-hydroxy-10α-methoxy-ergoline,

15) 8α-hydroxy-10β-hydroxy-ergoline,

16) 8α-hydroxymethyl-10α-methoxy-ergoline,

17) 8α-hydroxymethyl-10α-hydroxy-ergoline,

18) 6-methyl-8α-hydroxy-10α-methoxy-ergoline,

19) 6-methyl-8α-hydroxymethyl-10α-methoxy-ergoline,

20) 6-methyl-8α-hydroxy-10β-methoxy-ergoline,

21) 6-methyl-8α-hydroxymethyl-10β-methoxy-ergoline,

22) 6-methyl-8β-hydroxy-10β-methoxy-ergoline,

23) 6-methyl-8β-hydroxymethyl-10β-methoxy-ergoline,

24) 6-methyl-8β-(2-hydroxy)ethyl-10α-methoxy-ergoline,

25) 6-methyl-8β-(3-hydroxy)propyl-10α-methoxy-ergoline,

26) 6-methyl-8β-hydroxy-10α-(2-hydroxy)ethoxy-ergoline,

27) 6-methyl-8β-hydroxymiethyl-10α-(2-hydroxy)ethoxy-ergoline,

28) 6-methyl-8β-hydroxy-10α-(3-hydroxy)propoxy-ergoline,

29) 6-methyl-8β-hydroxymethyl-10α-(3-hydroxy)propoxy-ergoline,

30) 6-methyl-8β-hydroxy-10α-(2-methoxy)ethoxy-ergoline,

31) 6-methyl-8β-hydroxymethyl-10α-(2-methoxy)ethoxy-ergoline,

32) (2-hydroxy)ethyl-8β-hydroxy-10α-methoxy-ergoline,

33) (2-hydroxy)ethyl-8β-hydroxymethyl-10α-methoxy-ergoline,

34) (2-hydroxy-2-phenyl)ethyl-8β-hydroxy-10α-methoxy-ergoline

35) (2-hydroxy-2-phenyl)ethyl-8β-hydroxymethyl-10α-methoxy-ergoline

36) 2,3-dihydro-6-methyl-8β-hydroxy-10α-methoxy-ergoline,

37) 2,3-dihydro-6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline,

38) 2,3-dihydro-6-methyl-8β-(2-hydroxy)ethyl-10α-methoxy-ergoline,

39) 2,3-dihydro-6-methyl-8β-dimethylhydroxymethyl-10α-methoxy-ergoline,

40) 2,3-dihydro-6-methyl-8β-dimethylhydroxymethyl-10α-hydroxy-ergoline,

41) 6-methyl-8β-dimethylhydroxymethyl-10α-methoxy-ergoline,

42) 6-methyl-8β-diethylhydroxymethyl-10α-methoxy-ergoline,

43) 6-methyl-8β-diphenylhydroxymethyl-10α-methoxy-ergoline,

44) 6-methyl-8β-dimethylhydroxymethyl-10α-hydroxy-ergoline,

45) 6-methyl-8β-diethylhydroxymethyl-10α-hydroxy-ergoline,

46) 6-methyl-8β-diphenylhydroxymethyl-10α-hydroxy-ergoline,

47) 6-methyl-8α-dimethylhydroxymethyl-10α-methoxy-ergoline and6-methyl-8α-diphenylhydroxymethyl-10α-methoxy-ergoline.

The invention provides also a process for preparing compounds of formulaI of the present invention, depending on the nature of the substituents,starting from known ergolines by appropriate chemical modifications.

Processes for preparing compounds of formula I and pharmaceuticallyacceptable salt thereof are as follows:

(i) a preferred process for the preparation of a compound of formula Iwherein Z is a hydroxy group and the symbol--at 9, 10 position is asingle bond, or a pharmaceutically acceptable salt thereof, comprises

(1) reacting a compound of formula IIa ##STR3## wherein R₅ is C₁ -C₅alkyl group and--and R₁ and R₂ are defined above, with hydrazine andtreating the resultant 8-hydrazide derivative with a nitrite salt inacidic conditions,

(2) treating the resultant 8-amino derivative of the formula III##STR4## wherein--and R₁ and R₂ are as defined above, with a nitritesalt in the presence of acetic acid, and hydrolysing the resultant8-acetyloxy derivative and, if desired,

(3) converting a resultant compound of formula I ##STR5## wherein--andR₁ are as defined above and R₂ is a methyl group, into a compound offormula I wherein R₂ is different from methyl, by treatment with acompound of formula R₂ -OH in the presence of an acid, and, if desired,converting the resultant said compounds of formula I into apharmaceutically acceptable salt thereof.

(ii) In another example, a preferred process for the preparation of acompound of formula I wherein Z is a group of formula (CH₂)_(n) OH, withn 1 or 2, or a pharmaceutically acceptable salt thereof, comprises

(1) reducing a compound of formula II ##STR6## wherein--R₁, R₂ and R₅are as defined above, and, if desired, (2) treating the resultantcompound of formula I, wherein Z represents CH₂ OH, withmethanesulphonylchloride;

(3) reacting the resultant compound of formula IV ##STR7## wherein R₁,R₂ and--are as defined above, with KCN, (4) reacting with an acid theresultant compound of formula V ##STR8## wherein R₁, R₂, and--are asdefined above, in the presence of an alcohol of the formula R₅ -OH,wherein R₅ is as above defined;

(5) reducing the resultant compound of formula VI ##STR9## wherein R₁,R₂, R₅ and--are as defined above, and, if desired, converting theresultant compound of formula I wherein Z is CH₂ CH₂ OH or CH₂ OH, asobtained above under step (ii)(1) into a pharmaceutically acceptablesalt thereof.

(iii) In another example, a preferred process for the preparation of acompound of formula I wherein Z is CH₂ CH₂ CH₂ OH, or a pharmaceuticallyacceptable salt thereof, comprises:

(1) condensing a compound of formula IV as defined above with a di-C₁-C₅ alkylmalonate salt;

(2) heating the resultant compound of formula VII ##STR10## wherein R₁,R₂, R₅ and--are as defined above, (3) reducing the resultant compound offormula VIII ##STR11## wherein R₁, R₂, R₅ and--are as defined above,and, if desired, converting the resultant compounds of formula I into apharmaceutically acceptable salt thereof.

(iv) In another example, a preferred process for the preparation of acompound of formula I wherein Z is a group of formula C(R₄)₂ OH, whereinR₄ is as defined above, or a pharmaceutically acceptable salt thereof,comprises:

(1) condensing a compound of formula II as defined above with a Grignardreagent of formula R₄ MgBr wherein R₄ is as defined above, and, ifdesired, converting the resultant said compound of formula I into apharmaceutically acceptable salt thereof.

(v) In a further example, another process for the preparation of acompound of formula I wherein--at 8, 9 position is a single bond,comprises converting a compound of formula IX ##STR12## wherein--, R₁and Z are as above defined, by photochemical addition of a compound offormula R₂ -OH, wherein R₂ is as above defined, in the presence of anacid, and, if desired, converting the resultant said compounds offormula I into a pharmaceutically acceptable salt thereof.

It should be noted that, if desired, derivatives of formula I producedaccording to processes (i), (ii), (iii), (iv) and (v) can be furthermodified at different parts of the molecule by combining processes abovedescribed or by means of synthetic procedures known for the ergotderivatives.

The compounds of formula I as defined under (i) above may be preparedfor example by reacting a compound of formula IIa, as above defined,with hydrazine hydrate in ethanol at reflux; the corresponding hydrazidewas obtained that, by following treatment with sodium nitrite inpresence of hydrochloric acid at 0° C. and subsequent heating at 90-100°C., was converted into a compound of general formula III. (P. A. S.Smith, Org. React., 3, 337(1946)).

Subsequent treatment with sodium nitrite in glacial acetic acid at 5-10°C., afforded the corresponding acetyloxy derivative that was thensaponified with sodium hydroxide in ethanol or methanol at a temperatureranging from 35° to 70° C. to provide compounds of general formula I.When R₂ is a methyl group, these compounds can be converted intocompounds of general formula I, wherein R₂ is a group different frommethyl, by reaction with R₂ -OH in presence of 10-15% of acids such assulphuric, trifluoroacetic, methanesulphonic at 10°-35° C.

The compounds of formula I as defined above under (ii) may be preparedfor example by reducing a compound of formula II as defined above toafford a compound of general formula I, wherein n is 1. The reductioncan be carried out employing reducing agents such as LiAlH₄ in solventssuch as tetrahydrofuran or dioxane at 0°-50° C., or NaBH₄ in solventssuch as isopropanol, or methanol at 15°-70° C.

Subsequent reaction of compound of formula I, wherein n is 1, withmethanesulphonylchloride in pyridine at 0-5° C., provides compound offormula IV as above defined, that by reaction with KCN indimethylsulphoxide or dimethylformamide at 50-90° C. affords compound offormula V, as above defined. By reaction of compound of formula V withmethanol in presence of gaseous hydrochloric acid, a compound of formulaVI was obtained that by reduction as described above provided a compoundof formula I wherein n is 2. The compounds of formula I as defined under(iii) may be prepared, for example, condensing a compound of formula IV,as above defined, with sodiumdimethylmalonate in dimethylformamide at60°-85° C. to afford compound of formula VII, that by heating at100°-120° C. in dimethylsulphoxide in presence of sodium chloride wasconverted in compound of formula VIII, further reduction as abovedescribed of compound of formula VIII provided compound of formula Iwherein n is 3. (C. S. Marvel and F. D. Hager, Org. Synth., 1,248(1941)).

The compounds of formula I as defined under (iv) may be prepared, forexample, condensing a compound of formula II as above defined with aGrignard reagent R₄ MgBr in a solvent such as diethylether ortetrahydrofuran at 0°-55° C.(W. W. Moyer and C. S. Marvel, Org. Synth.,2, 602(1943)). The compounds of formula I as defined under (v) may beprepared, for example, by converting a compound of formula IX as definedabove into a compound of formula I by photochemical addition of R₂ OH tothe double bond in presence of diluted sulphuric acid at 10-40° C.employing Hg/medium pressure lamp.

Some of the starting materials for the preparation of compounds offormula I are known. Other may be analogously prepared starting fromknown compounds by means of known procedures. The known compounds offormula I are described only as intermediate for the preparation ofbiological active ergoline compounds in U.S. Pat. No. 3,228,943, EP-A-0004 664, EP-A-O-156 645 and U.S. Pat. No. 4,861,793, wherein a processfor their preparation is also described.

It has been found that the ergoline derivatives of formula I may beunexpectedly used in the treatment of neurodegenerative pathologiesassociated either with a diminished PKC activity as in the case ofAlzheimer's disease or Down' syndrome, age related memory impairment orage related learning disturbances.

The compounds of formula I are able to enhance in vitro thephosphorylation of the endogenous substrate for PKC: B-50/GAP-43mimicking closely the in vivo situation.

Moreover, the compounds of formula I are able to increase the PKCtranslocation in synaptosomes of different brain area such ashippocampus and striatum.

The compounds of the present invention could be therefore employed inthe treatment of pathologies associated with a reduced functionality ofthe PKC signal transduction pathway such as various forms of dementia,memory disturbances, Alzheimer's disease and Down's syndrome.

The toxicity of the compounds of the present invention is quitenegligible, being >800 mg/Kg p.o., and they are therefore safelyemployable as useful drugs.

Experimental Part-Biological Data

Phosphorylafion of B-50/GAP-43

B-50 purified from rat brain according to Graan T et al. (De Graan P. N.E., Moritz A., De Wit M. and Gispen W. H. Purification of B-50 by2-mercaptoethanol extraction from rat brain synaptosomal plasmamembranes, Neurochem Res 18:875-881, 1993) was utilised as substrate.The protein was phosphorylated by PKC purified according to Kikkawa etal (Kikkawa U., Go M., Kuomoto J. and Nishizuka Y. Rapid purification ofPKC by HPLC, Biochim Biophys Res Commun 135:636-643, 1986) (0.012 μg/1μg substrate/7.5 μM ATP, 1 μCi/tube) in a reaction mixture containing 20mM Tris Hcl pH 7.0, 10 mM MgCl₂, 0.2 mM CaCl₂, 1 μg/100 μl PS. γ ³²P-ATP has been utilised as phosphate donor. The incubation was carriedout at 30° C. for 5 min., then the reaction was stopped by adding 1/3volume of a stopping solution containing: 3% Sodium Dodecyl Sulphate(SDS), 5% 2-mercaptoethanol, 10% glycerol, 0.002% bromophenolblue in0.12 M TrisHCl pH 6.8. Samples were then subjected to one dimensionalSDS-Polyacrylamide gel electrophoresis (PAGE) using 11% acrylamide--0.3%bis-acrylamide in the resolving gel. The resulting gel was stained,destained and autoradiographed. Quantitative analysis of B-50 band inthe autoradiogram has been performed by densitometric analysis.

    ______________________________________                                        CONTROL                   100%                                                  6-Methyl-8β-hydroxymethyl-10α-methoxy-ergoline 108%              ______________________________________                                    

Compounds of the invention are able to increase the in vitrophosphorylation of a specific presynaptic substrate for PKC, the growthassociated protein B-50, known to play a key role in different phases oftransmission during synaptic plasticity associated events.

PKC Translocation in Different Brain's Area

Purified synaptosomes have been obtained following the proceduredescribed by Dunkley (Dunkley P. R., Health J. W:, Harrison S. M.,Jarvie P. E., Glenfield P. J. and Rostas J. A. P. A rapid percolationgradient procedure for isolation of synaptosomes directly from S1fraction: homogeneity and morphology of subcellular fractions. Brain res441:59-71, 1988).

Synaptosomes purified from cortex, hippocampus were incubated (10 mg/ml)for 15 min at 30° C. in presence of increasing doses of the compounds ofthe present invention dissolved in tartaric acid (pH 7.0) or of thevehicle alone. After incubation, purified synaptosomes were collected incold Krebs buffer containing 10 mM EGTA and then processed according toShearmann et al (Sheannan M. S., Shinomura T., Oda T. and Nishizuka Y.Protein kinase C subspecies in adult rat hippocampal synaptosomes.Activation by diacylglycerol and arachidonic acid. FEBS Lett279:261-264, 1991).

Synaptosomes have been lysed in this solution for 30 min at 4° C. withstirring. The lysed suspension was centrifuged at 100000 g for 60 min.The resultant supernatant was processed as "cytosolic fraction". Thepellet was again resuspended in lysis buffer containing 0.1% TritonX-100 at 4° C. for 45 min. The centrifugation step was repeated and theresulting supernatant represents the "membrane fraction". Proteinspresent in the cytosolic and membrane fractions were separated bySDS-PAGE and blotted on nitrocellulose paper. PKC on Western blots wasdetected with a polyclonal total PKC antibody (Upstate Biotechnology).Western blot analysis of PKC isozymes has been performed utilizingmonoclonal antibodies (GIBCO). Antigen antibody complexes were detectedby enhanced chemiluminescence. Results have been analysed by computerassisted Image analysis and expressed as per cent of PKC translocationin control conditions.

Data of the PKC translocation in hippocampal synaptosomes of compound ofthe invention are shown in the following table:

    ______________________________________                                        CONTROL                      100                                                6-Methyl-8β-hydroxymethyl-10α-methoxy-ergoline 10.sup.-5 M                                    139                                                6-Methyl-8β-hydroxyl-10α-methoxy-ergoline 10.sup.-5 M 153                                      6-Methyl-8β-hydroxymethyl-10β-meth                                 oxy-ergoline 10.sup.-5 M 156                       6-Methyl-8β-hydroxymethyl-10α-hydroxy-ergoline 10.sup.-5 M                                    190                                                8β-Hydroxymethyl-10α-hydroxy-ergoline 10.sup.-5 M 190                                          6-Methyl-8β-hydroxymethyl-10α-(2-                                 hydroxyethyl)- 162                                 ergoline 10.sup.-5 M                                                          6-Methyl-8β-(2-hydroxy)ethyl-10α-methoxy-ergoline 10.sup.-5                                   M 193                                            ______________________________________                                    

In a physiological assay using purfied and viable synaptosomes, thecompounds of the invention are able to increase the translocation of PKCto the membrane compartment. These results are of particular interestconsidering that the concentration of PKC is significantly reduced inthe particulate fraction of various regions of Alzheimer's diseasebrain) Masliah E., Cole G., Shimohama S., Hansen L., De Teresa R., TerryR. D. and Saitob T. Differential involvement of protein kinase Cisozymes in Alzheimer's disease. J Neurosci 10:2113-2124, 1990).

The present invention also includes pharmaceutical composition ofcompounds of formula I in association with a pharmaceutically acceptableexcipient (which can be carrier or diluent). The pharmaceuticalcomposition containing the compounds of the invention are usuallyprepared following conventional methods and are administered in apharmaceutically suitable form. For example, the solid oral form maycontain, together with the active compound, diluents, e.g. lactose,dextrose, cellulose, corn starch or potato starch; lubricants, e.g.silica, talc, stearic acid, magnesium or calcium stearate, and/orpolyethylene glycols; binding agents, e.g. starches, arabic gums,gelatins, methylcellulose or polyvinyl pirrolidone; and, in general, nontoxic and inactive substances used in pharmaceutical formulations. Thesepharmaceutical preparations may be manufactured in known manner, forexample, by means of mixing, granulating, tabletting sugar-coated, orfilm-coating processes.

A tablet formulation may be prepared as follow:

    ______________________________________                                                        Quantity (mg/tablet)                                          ______________________________________                                        ACTIVE INGREDIENT  25                                                           STARCH DRIED 425                                                              MAGNESIUM STEARATE  10                                                        TOTAL 460                                                                   ______________________________________                                    

The above ingredients are blended together and compressed to formtablets each weighting 460 mg.

The liquid dispersion for oral administration, may be e.g. syrup,emulsions or suspensions. The syrups may contain as carrier, forexample, saccharose or saccharose with glycerine and/or mannitol and/orsorbitol. The suspensions and the emulsions may contain as carrier, forexample, a natural gum, agar, sodium alginate, pectine or polyvinylalcohol. The suppositories may contain together with the active compounda pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylenglycol, or lecithin. In general, the drugs may be administered assingler dose or as divided dose so as to provide, say, about 5-50 mg/Kgbody weight per day of effective ingredients, preferably 5-15 mg/Kg bodyweight.

The following examples illustrate the invention

EXAMPLE 1

6-Methyl-8β-(3-hydroxy)propyl-10α-methoxy-ergoline

(R₁ =CH₃, R₂ =CH₃, --(2,3)==, --(8,9)=--, Z=(CH₂)₃ OH)

A stirred mixture of 4.3 g of6-methyl-8β-tosyloxymethyl-10α-methoxy-ergoline, 2.5 g of sodium diethylmalonate and 1.5 g of potassium iodide in 30 ml of dimethylsulphoxideand 10 ml of diethyl malonate were heated at 75° C. for 2 hours.

The solution was poured in ice water and the resultant precipitate wasfiltered off, dried and chromatographed on a silica gel column usingethylacetate as eluant. The combined fractions were evaporated todryness and crystallised from ethanol to give 3.2 g of2-ethoxycarbonyl-3-(6-methylergolin-10α-methoxy-8β-yl)-propionic acidethyl ester.

A stirred solution of 15 g of2-ethoxycarbonyl-3-(6-methylergolin-10α-methoxy-8β-yl)-propionic acidethyl ester and 15 g of anhydrous sodium chloride in 100 ml ofdimethylsulphoxide was heated at 180° C. for 1 hour. The solvent wasremoved in vacuum and the residue was taken up in ethylacetate andwashed several times with brine. After drying and removal of thesolvent, the residue was crystallised twice from ethanol to give 11 g of3-(6-methylergolin- 10α-methoxy-8β-yl)-propionic acid ethyl ester.

To a stirred suspension of 5 g of lithium aluminium hydride in 150 ml oftetrahydrofuran was added portionwise 15 g of3-(6-methylergolin-10α-methoxy-8β-yl)-propionic acid ethyl ester at 25°C.

After stirring for 5 hours, the excess of the hydride was destroyed bycarefully addition of 10 ml of water. The suspension was filtered thenthe solvent was removed.

The residue was dissolved in methanol, charcoalised then crystallisedfrom ethanol to afford 9.6 g of the title compound, m.p.190-195° C.

EXAMPLE 2

6-Methyl-8β-hydroxvmethyl-10α-(2-hydroxy)ethoxy-ergoline

(R₁ =CH₃, R₂ =CH₂ CH₂ OH, --(2,3)==, --(8,9)=--, Z=CH₂ OH)

A stirred solution of 10 g of6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline in 100 ml of ethylenglycol was treated with 7.5 ml of concentrated sulphuric acid at roomtemperature. After stirring for 3 hour, the solution was poured into icewater then made alkaline with concentrated sodium hydroxyde. Theprecipitated was collected washed with water, and crystallised fromehanol to provide the title compound in 75% yield, m.p. 201-205° C.

EXAMPLE 3

6-Methyl-8β-hydroxymethyl-10α-(2-hydroxy)ethoxy-ergoline

(R₁ =CH₃, R₂ =CH₂ CH₂ OH, --(2,3)==, --(8,9)=--, Z=CH₂ OH)

Operating as in Example 2, but employing6-methyl-8α-hydroxymethyl-10α-methoxy-ergoline instead of6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline, the title compound wasobtained in 60% yield, m.p. 178-180° C.

EXAMPLE 4

6-Methyl-8β-hydroxymethyl-10α-(3-hydroxy)propoxy-ergoline

(R₁ =CH₃, R₂ =CH₂ CH₂ CH₂ OH, --(2,3)==, --(8,9)=--, Z=CH₂ OH)

Operating as in Example 2, but employing 1,3-propandiol instead ofethylen glycol, the title compound was obtained in 55% yield, m.p.189-195° C.

EXAMPLE 5

6-Methyl-8α-(3-hydroxy)protyl-10α-methoxy-ergoline

(R₁ =R₂ =CH₃, --(2,3)==, --(8,9)=--, Z=(CH₂)₃ OH)

Operating as in Example 1, but employing6-methyl-8α-tosyloxymethyl-10α-methoxy-ergoline, instead6-methyl-8β-tosyloxymethyl-10α-methoxy-ergoline, the title compound wasobtained in 35% yield, m.p. 134-138° C.

EXAMPLE 6

6-Methyl-8β-(3-hydroxy)propyl-10α-(2-hydroxy)ethoxy-ergoline

(R₁ =CH₃, R₂ =CH₂ CH₂ OH, --(2,3)==, --(8,9)=--, Z=(CH₂)₃ OH)

Operating as in Example 2, but employing6-methyl-8β-(3-hydroxy)propyl-10α-methoxy-ergoline instead of6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline, the title compound wasobtained in 57% yield, m.p. 212-215° C.

EXAMPLE 7

6-Methyl-8β-hydroxymethyl-10α-(2-methoxy)ethoxy-ergoline

(R₁ =CH₃, R₂ =CH₂ CH₂ OCH₃, --(2,3)==, --(8,9)=--, Z=CH₂ OH)

Operating as in Example 2, but employing 2-methoxyethanol instead ofethylen glycol, the title compound was obtained in 67% yield, m.p.188-193° C.

EXAMPLE 8

6-Methyl-8β-hydroxymethyl-10α-hydroxy-ergoline

(R₁ =CH₃, R₂ =OH, --(2,3)==, --(8,9)=--, Z=CH₂ OH)

Operating as in Example 2, but employing water instead of ethylenglycol, the title compound was obtain in 85% yield, m.p. 175-179°.

EXAMPLE 9

6-Methyl-8β-hydroxymethyl-10β-hydroxy-ergoline

(R₁ =CH₃, R2=OH, --(2,3)==, --(8,9)=--, Z=CH₂ OH)

From the mother liquor of the preparation of6-methyl-8β-hydroxymethyl-10α-hydroxy-ergoline, the title compound wasrecovered in 5% yield, m.p. 134-137° C.

EXAMPLE 10

8β-Hydroxymethyl-10α-hydroxy-ergoline

(R₁ =H, R2=OH, --(2,3)==, --(8,9)=--, Z=CH₂ OH)

Operating as in Example 8, but employing8β-hydroxymethyl-10α-methoxy-ergoline instead of6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline, the title compound wasobtained in 65% yield, m.p. 145-149° C.

EXAMPLE 11

8β-Hydroxymethyl-10α-(2-hydroxy)ethoxy-ergoline

(R₁ =H, R₂ =CH₂ CH₂ OH, --(2,3)==, --(8,9)=--, Z=CH₂ OH)

Operating as in Example 2, but employing8β-hydroxymethyl-10α-methoxy-ergoline instead of6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline, the title compound wasobtained in 75% yield, m.p. 198-205° C.

EXAMPLE 12

6-Methyl-8β-dimethylhydroxymethyl-10α-methoxy-ergoline

(R₁ =CH₃ ; R₂ =CH₃, --(2,3)==, --(8,9)=--, Z=(CH₃)₂ COH)

To a solution of 5 g of 6-methyl-8β-methoxycarbonyl-10α-methoxy-ergolinein 100 ml of tetrahydrofuran were added dropwise 25 ml of 1M solution ofmethyl magnesium iodide in tetrahydrofuran.

The suspension was refluxed for 2 hours, then treated with 25 ml of asaturated solution of ammonium chloride.

After filtration, the solvent was removed and the residue taken up indichloromethane, drying, removal of the solvent and subsequentcrystallisation from acetone afforded 3.7 g of the title compound,m.p.141-147° C.

EXAMPLE 13

6-Methyl-8β-dimethylhydroxymethyl-10α-(2-hydroxy)ethoxy-ergoline

(R₁ =CH₃ ; R₂ =CH₂ CH₂ OH, --(2,3)==, --(8,9)=--, Z=(CH₃)₂ COH)

Operating as in Example 2, but employing6-methyl-8β-dimethylhydroxymethyl-10α-methoxy-ergoline instead of6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline, the title compound wasobtained in 43% yield, m.p. 178-184° C.

EXAMPLE 14

6-(2-Hydroxy)ethyl-8β-hydroxymethyl-10α-methoxy-ergoline

(R₁ =CH₃, R₂ =CH2CH₂ OH, --(2,3)==, --(8,9)=--, Z=CH₂ OH)

To a stirred solution of 3 g of 8β-hydroxymethyl-10α-methoxy-ergoline, 3g of potassium carbonate in 25 ml of dimethylformamide was added 1.3 gof 2-bromoethanol.

After stirring for 3 hours at room temperature, the solution was dilutedwith ethylacetate and thoroughly washed with brine, after drying thesolvent was removed and the residue chromatographed on a small pad ofsilica to provide after crystallisation from ethanol 2.1 g of the titlecompound, m.p. 198-204° C.

EXAMPLE 15

2.3β-dihydro-6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline

(R₁ =CH₃, R₂ =CH₃, --(2,3)=--, --(8,9)=--, Z=CH₂ OH)

To a stirred solution of 5 g of6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline in 35 ml oftrifluoroacetic acid was carefully added portionwise under a stream ofnitrogen, 0.7 g of sodiumborohydride.

After 10 minutes of stirring, the solution was diluted with ice water,basified with ammonia and extracted with dichloromethane. After dryingand removal of the solvent, the residue was columned on silica geleluting with chloroform to afford after crystallisation fromethylacetate 1.3 g of the title compound, m.p.134-138° C.

EXAMPLE 16

2,3α-dihydro-6-methyl-8β-hydroxymethyl-10α-methoxy-ergolin

(R₁ =CH₃, R₂ =CH₃, --(2,3)=--, --(8,9)=--, Z=CH₂ OH)

The mother liquor of the crystallization of compound 15 were carefullychromatographed on silica gel eluting with chloroform/methanol 9/1,affording after crystallization from isopropanol the title compound,m.p.97-102° C.

We claim:
 1. A method of treating neurodegenerative diseases, comprisingadministering to a patient in need thereof an effective amount of anergoline derivative represented by formula I: ##STR13## wherein R₁represents a hydrogen atom or a linear or branched C₁ -C₅ alkyl or C₂-C₅ alkenyl group optionally substituted with a C₃ -C₇ cycloalkyl, ahydroxy group or a R₃ -substituted phenyl group wherein R₃ is a hydroxyor a hydroxymethyl group;R₂ represents a hydrogen atom or a linear orbranched C₁ -C₅ alkyl or a C₂ -C₅ alkenyl group optionally substitutedwith a hydroxy group, or a R₃ -substituted phenyl group wherein R₃ isabove defined, or with a C₁ -C₅ alkoxy group; the symbols--at positions2, 3 and 8, 9 independently denote a single or double chemical bond andZ represents a group (CH₂)_(n) OH, wherein n is 0 or an integer from 1to 3, or a group C(R₄)₂ OH wherein R₄ is a C₁ -C₅ alkyl, or a phenylgroup, or a pharmaceutically acceptable salt thereof.
 2. The method ofclaim 1, wherein R₁ is a hydrogen atom, methyl, 2 hydroxyethyl or(2-hydroxy-2-phenyl)ethyl group; R₂ is hydrogen atom or methyl,1-methylethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethylgroup, Z is a group (CH₂)_(n) OH, or C(R₄)₂ OH, n is 0, 1 or 2, R₄ ismethyl or phenyl group.
 3. The method of claim 1, wherein theneurodegenerative diseases are selected from the group consisting ofAlzheimer's diseases, Down's syndrome, dementia, and memory impairment.4. An ergoline derivative formula represented by formula I: ##STR14##wherein R₁ represents a hydrogen atom or a linear or branched C₁ -C₅alkyl or C₂ -C₅ alkenyl group optionally substituted with a C₃ -C₇cycloalkyl, a hydroxy group or a R₃ -substituted phenyl group wherein R₃is a hydroxy or a hydroxymethyl group;R₂ represents a hydrogen atom or alinear or branched C₁ -C₅ alkyl or a C₂ -C₅ alkenyl group optionallysubstituted with a hydroxy group, or a R₃ -substituted phenyl groupwherein R₃ is above defined, or with a C₁ -C₅ alkoxy group; thesymbols--at positions 2, 3 and 8, 9 independently denote a single ordouble chemical bond and Z represents a group (CH₂)_(n) OH, wherein n is0 or an integer from 1 to 3, or a group C(R₄)₂ OH wherein R₄ is a C₁ -C₅alkyl or a phenyl group, or a pharmaceutically acceptable salt thereof,with the proviso that the following compounds areexcluded:6-methyl-8β-hydroxy-10α-methoxy-ergoline,6-methyl-8β-hydroxymethyl-10β-methoxy-ergoline,6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline,6-methyl-8α-hydroxymethyl-10α-methoxy-ergoline,6-methyl-8β-hydroxymethyl-10α-(methylethoxy)-ergoline,6-methyl-8β-hydroxymethyl-10α-hydroxy-ergoline,6-methyl-8β-hydroxymethyl-10β-hydroxy-ergoline,6-methyl-8β-hydroxymethyl-10α-methoxy-Δ-8,9-ergoline,8β-hydroxymethyl-10α-methoxy-ergoline,6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline, and6-methyl-8β-hydroxymethyl-10α-propoxy-ergoline.
 5. The ergolinederivative of claim 4, wherein Z is not a hydroxy, hydroxymethyl orhydroxyethyl group when R₁ is hydrogen, or a methyl, propyl group, R₂ ishydrogen or a methyl, propyl, isopropyl group, --at the 2, 3 position isa double bond and--at the 8, 9 position represents a single or a doublebond.
 6. A process for preparing the ergoline derivative of claim 4,wherein Z is a hydroxy group and the symbol--at 8, 9 position is asingle bond, or a pharmaceutically acceptable salt thereof, whichcomprises:(1) reacting a compound of formula represented by formula IIa:##STR15## wherein R₅ is C₁ -C₅ alkyl group and--and R₁ and R₂ are asdefined in claim 4, with hydrazine, and treating the resulting8-hydrazide derivative with a nitrite salt in acidic conditions, (2)treating the resulting 8-amino derivative represented by formula III:##STR16## wherein--and R₁ and R₂ are as defined above, with a nitritesalt in the presence of acetic acid, and hydrolyzing the resultant8-acetyloxy derivative and, optionally, (3) converting the resultingcompound represented by formula I: ##STR17## wherein Z is a hydroxygroup and the symbol--at 8, 9 position is a single bond, and R₁ is asdefined above and R₂ is methyl group, into a compound represented byformula I wherein R₂ is different from methyl, by treating with acompound represented by formula R₂ -OH in the presence of an acid, and,optionally, converting the resulting compound represented by formula Iinto a pharmaceutically acceptable salt thereof.
 7. A process forpreparing the ergoline derivative of claim 4, wherein Z is a group offormula (CH₂)_(n) OH, with n 1 or 2, or a pharmaceutically acceptablesalt thereof, which comprises:(1) reducing a compound represented byformula II: ##STR18## wherein--R₁ and R₂ are as defined in claim 4, andR₅ is C₁ -C₅ -alkyl, and, optionally, (2) treating the resultingcompound represented by formula I, wherein Z represents CH₂ OH, withmethanesulphonylchloride; (3) reacting the resulting compoundrepresented by formula IV ##STR19## wherein R₁, R₂ and--are as definedabove, with KCN, (4) reacting with an acid the resulting compoundrepresented by formula V ##STR20## wherein R₁, and R₂, and--are asdefined above, in the presence of an alcohol represented by the formulaR₅ -OH, wherein R₅ is as above defined; (5) reducing the resultantcompound of formula VI ##STR21## wherein R₁, R₂, R₅ and--are as definedabove, and, optionally, converting the resulting compound of formula Iwherein Z is CH₂ CH₂ OH or CH₂ OH, as obtained above under step (1),into a pharmaceutically acceptable salt thereof.
 8. A process forpreparing ergoline derivative of claim 4, wherein Z is CH₂ CH₂ CH₂ OH,or a pharmaceutically acceptable salt thereof, which comprises:(1)condensing a compound represented by formula IV ##STR22## with a di-C₁-C₅ -alkylmalonate salt; (2) heating the resulting compound representedby formula VII: ##STR23## wherein R₁, R₂, R₅ and--are as defined above,(3) reducing the resulting compound represented by formula VIII:##STR24## wherein R₁, R₂, R₅ and--are as defined above, and, optionally,converting the resulting compound of formula I into a pharmaceuticallyacceptable salt thereof.
 9. A process for preparing the ergolinederivative of claim 4, wherein Z is a group of formula (C(R₄)₂ OH,wherein R₄ is as defined in claim 4, or a pharmaceutically acceptablesalt thereof, which comprises: ##STR25## with a Grignard reagentrepresented by the formula R₄ MgBr wherein R₄ is as defined above, andoptionally, converting the resulting compound represented by formula Iinto a pharmaceutically acceptable salt thereof.
 10. A process forpreparing the ergoline derivative of claim 4, wherein--at 8, 9 positionis a single bond, which comprises converting a compound represented byformula IX ##STR26## wherein--, R₁ and Z are as defined in claim 4, byphotochemical addition of a compound represented by formula R₂ -OH,wherein R₂ is as defined in claim 4, in the presence of an acid, and,optionally, converting the resulting compounds represented by formula Iinto a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticallycomposition which comprises, as an active ingredient, a therapeuticallyeffective amount of an ergoline represented by formula I as defined inclaim 4, or a pharmaceutically acceptable salt thereof, in admixturewith a pharmaceutically acceptable carrier or diluent.
 12. A method oftreating neurodegenerative diseases, comprising administering to apatient in need thereof an effective amount of the ergoline derivativeof formula I as defined in claim 4 or a pharmaceutically acceptable saltthereof.